The present invention relates to novel substituted 1,3-cycloalkenes and cycloalkanes useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are dopaminergic agents.
A series of substituted cyclohexenes represented by the Formula I ##STR1## wherein R.sup.1 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or 3- thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3- furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen;
m is zero or an integer from one to two; R.sup.2 is ##STR2## wherein R.sup.1 is as defined above; n is zero or an integer from one to four; and PA1 corresponding optical isomers thereof; or a pharmaceutically acceptable acid addition salt thereof, useful as dopaminergic agents, is disclosed in U.S. Pat. No. 4,975,445. PA1 A is 5-7C cycloalkyl or cycloalkenyl, or --(CH.sub.2).sub.n --CHR.sup.5 --; PA1 n is 1, 2, or 3; PA1 R.sup.5 is R.sup.1 ; PA1 R.sup.6, R.sup.7 is H or Me; or PA1 R.sup.4 +R.sup.7 is a methylene bridge or a pharmaceutically acceptable acid addition salt useful in the treatment of depression, anxiety, and panic disorders is disclosed in European Patent Application EP-345,808A. PA1 Z is ##STR4## wherein R is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, hydroxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, hydroxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, hydroxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen, 3-indolyl, 2-, 3-, or 4-quinolinyl, and PA1 m is an integer of 1, 2, or 3, ##STR5## wherein R and m are as defined above, ##STR6## wherein R and m are as defined above, or ##STR7## wherein R is as defined above; Y is ##STR8## wherein R is as defined above or ##STR9## wherein R is as defined above; and corresponding isomers thereof; or a pharmaceutically acceptable acid addition salt thereof. PA1 Z.sup.a is ##STR22## wherein R is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, hydroxy, or halogen, 2-, 3-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, hydroxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, hydroxy, or halogen, 2-, or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen, 3-indolyl, 2-, 3-, or 4-quinolinyl, and m is an integer of 1, 2, or 3, and ##STR23## wherein R and m are as defined above; Y is ##STR24## wherein R is as defined above or ##STR25## wherein R is as defined above; and corresponding isomers thereof; or a pharmaceutically acceptable acid addition salt thereof may be prepared by reacting a compound of Formula II ##STR26## wherein m and Y are as defined above with a compound of Formula III EQU R-M III PA1 Z.sup.b is ##STR27## wherein R and m are as defined above; Y.sup.a is ##STR28## wherein R is as defined above; and corresponding isomers thereof; or a pharmaceutically acceptable acid addition salt thereof may be prepared by reacting a compound of Formula Ic EQU Z.sup.a --CH.sub.2 --Y.sup.a Ic PA1 wherein Z.sup.a and Y.sup.a are as defined above with hydrogen in the presence of a catalyst such as, for example, palladium on carbon and the like in a solvent such as, for example, methanol and the like to afford a compound of Formula Ib. Preferably, the reaction is carried out with palladium on carbon in methanol.
A series of 1-indolylalkyl-4-substituted pyridinyl piperazines represented by Formula I ##STR3## R.sup.1, R.sup.2 is H or 1-4C alkyl; R.sup.3, R.sup.4, R.sup.8, R.sup.9 is H, lower alkyl, lower alkoxy, carbamide, halo, CF.sub.3, or thio-lower alkyl; provided that R.sup.9 and R.sup.9 are not both H;
However, the compounds disclosed in the aforementioned references do not disclose or suggest the combination of structural variations of the compounds of the present invention described hereinafter.